Our long-term goals are to determine the detailed mechanisms that lead to irreversible shock and death in patients who cannot mount a glucocorticoid response after hemorrhage. These patients include, not only adrenalectomized or Addisonian subjects, but also patients exposed to stress and trauma after cessation of long term glucocorticoid treatment and normal patients subjected to acute and profound shock. The experimental design revolves around a well characterized chronically cannulated conscious adrenalectomized rat model that we have developed over the last 6 years. When fasted for 24 hours and then subjected to 15ml/kg*3min hemorrhage, arterial blood pressure recovers over the initial 60-90 minutes, then slowly decays into shock and death. The response in plasma ACTH, vasopressin, oxytocin, oxytocin, renin and norepinephrine and heart rate are markedly potentiated. We propose to study the mechanisms that lead to shock and death in this model in a four part experiment. 1) Using radiolabeled microspheres, we will determine if blood flow to various organs is compromised or altered after hemorrhage AND we will determine if hemorrhage in this model leads to liver failure. 2) By pretreating this model with pharmacological blocking agents to vasopressin, renin and/or norepinephrine prior to hemorrhage, we will determine if these hormones are involve in a) any alteration in organ blood flow and b) the slow decay of arterial blood pressure and death. 3) We will determine if systemic Interleukin-1- or Tumor Necrosis Factor are elevated after hemorrhage AND if systemic endotoxin levels are elevated suggesting bacterial translocation. 4) Using the Interleukin-1 receptor antagonist, passive immunization of Interleukin-6, and pentoxifyline (TNF production inhibitor), we will determine if Interleukin-1, Interleukin-6 or Tumor Necrosis Factor is involved in a) the decay of arterial blood pressure and death following hemorrhage, b) the potentiation of plasma vasopressin, renin and norepinephrine and c) any change in organ blood flow. Also, we will determine if prostaglandins or histamines are involved in the decay of arterial blood pressure and death following hemorrhage using cyclo- oxygenase inhibitors and H1 and H2 blockers.